Alzheimer's disease (AD) is the most prevalent old age-associated neurodegenerative disease. However, despite extensive interest and financial outlay, drug discovery in this area has not yet yielded any disease modifying compounds. This may be in part due to the small number of molecular targets suitable for drug discovery. Thus, the identification of multiple, new drug targets is still one of the most important challenges. Natural products are the structural basis of the majority of the drugs in the clinic today. Over the last decade we have used a novel phenotypic drug-screening platform based upon toxicities associated with the old brain and natural product chemical libraries and plant extracts to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Structure-activity relationship driven medicinal chemistry was then used to make pharmacologically suitable drug candidates. One of these compounds is in Phase I clinical trials for AD and another has NIH funding for investigational new drug (IND) studies. Perhaps the greatest relatively unexplored area of AD drug discovery is the endocannabinoid system and the compounds in the Cannabis plant that may interact with it and other pathways associated with neurodegeneration. While THC and CBD are the best-studied chemicals in Cannabis, there are over 100 non-psychoactive cannabinoids and 400 other unique chemicals within the plant that may have therapeutic potential. We have recently demonstrated that several of these compounds are exceptionally neuroprotective in our drug screening platform that has already yielded bona fide AD drug candidates. The hypothesis for this high risk, high reward R21 application is that there are non-psychoactive compounds within the Cannabis plant that are suitable lead drug candidates for AD, and that these can be identified, along with their molecular targets, by our drug screening platform and chemical proteomics, respectively. There are three Specific Aims in this application. 1) All commercially available pure cannabinoids, flavones and terpenes in Cannabis, will be screened, a project already underway. In collaboration with Dr. ElSohly at the University of Mississippi, additional pure compounds will be screened that he has isolated as well as complex high CBD Cannabis (hemp) extracts where the most active new compounds will be identified. The pharmacological and safety properties of the five best compounds will be studied. 2) The molecular targets of one will be determined. 3) Finally, the therapeutic efficacy of the best compound will be examined in the 3xFAD transgenic mouse model of familial AD and rapidly aging SAMP8 mice. At the end of two years, a non-psychoactive compound and its target will have been identified and tested in two rigorous models of dementia, gaining a greater understanding of the therapeutic potential of Cannabis as well as identifying a novel lead AD drug candidate and its molecular target.